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Dan Hultmark Professor of Medical Molecular Biology, Chairman UCMP Address: UCMP,
By. 6L
Umeå
University
S-901
87 Umeå
Sweden
E-mail:
dan.hultmark@ucmp.umu.se
Phone:
+46-90-785 67 78
Fax:
+46-90-77 80 07
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Present members of the lab
Ines Anderl, graduate student
Karin Borge Renberg, graduate student Jens-Ola Ekström, postdoc Karin Ekström, technician Mazen Habayeb, graduate student AnnaKarin Kronhamn, technician Jesper Kronhamn, postdoc Martin Schmid, graduate student Magda-Lena Wiklund, graduate student Michael Williams, postdoc |
 GFP-labeled blood cells (green) attack a parasitic wasp egg (black) inside a living Drosophila larva. |
 Closeup of encapsulated wasp egg with GFP-labelled hemocytes. |
Research projects: the
immune response in Drosophila
Our research is focused on the mechanisms of innate immunity, using Drosophila as a model system. This organism lacks lymphocytes and an acquired immune response, but has a well developed innate immune system. Studies of Drosophila have already contributed significantly to our understanding of innate immunity in humans. In addition, insect immunity is of great theoretical and practical importance in its own right, not least because insects are vectors for serious human diseases, and because insect pathogens are increasingly used to control agricultural pests.
The antibacterial response. When infected, insects synthesize a powerful set of antibacterial proteins and peptides such as the cecropins, first discovered in the cecropia moth. They provide a rapid broad-spectrum protection against bacteria as well as fungi. Genes for many of the antibacterial peptides in Drosophila have previously been characterized in our lab. We now focus our attention on the recognition and signaling events that lead to the induction of these genes.
The cellular response. Blood cells, called hemocytes, patrol the hemocoel in Drosophila. They phagocytize bacteria and other foreign particles, and they form capsules around parasites. They are also involved in the deposition of black melanin in the capsules and at wound sites. We are interested in the interactions between hemocytes and pathogenic organisms, and in how the encapsulation response is controlled.
Our research is focused on the mechanisms of innate immunity, using Drosophila as a model system. This organism lacks lymphocytes and an acquired immune response, but has a well developed innate immune system. Studies of Drosophila have already contributed significantly to our understanding of innate immunity in humans. In addition, insect immunity is of great theoretical and practical importance in its own right, not least because insects are vectors for serious human diseases, and because insect pathogens are increasingly used to control agricultural pests.
The antibacterial response. When infected, insects synthesize a powerful set of antibacterial proteins and peptides such as the cecropins, first discovered in the cecropia moth. They provide a rapid broad-spectrum protection against bacteria as well as fungi. Genes for many of the antibacterial peptides in Drosophila have previously been characterized in our lab. We now focus our attention on the recognition and signaling events that lead to the induction of these genes.
The cellular response. Blood cells, called hemocytes, patrol the hemocoel in Drosophila. They phagocytize bacteria and other foreign particles, and they form capsules around parasites. They are also involved in the deposition of black melanin in the capsules and at wound sites. We are interested in the interactions between hemocytes and pathogenic organisms, and in how the encapsulation response is controlled.
On-going research
Signal transduction pathways of the immune response. Two major signaling pathways for the immune response are now relatively well established in Drosophila, both of which rely on transcription factors of the NF-kB/Rel family. One pathway mediates signals from the membrane receptor Toll and leads to activation of the transcription factor Dif. We could early demonstrate the involvement of Toll in immune responses, but most of our research has been focused on the second pathway, which is of major importance in the induction of the antimicrobial response. It involves another transcription factor, Relish, first discovered in our lab. We later showed that Relish is activated via a novel proteolytic mechanism which requires the caspase Dredd. We are now focusing on the role of these and other pathways in cellular immunity. We are particularly interested in how hemocytes are activated in response to parasites. For this purpose we use Drosophila transgenic technology and genetic screens to identify the receptors and signaling pathways involved.
Specific recognition: hemocyte surface proteins. The PGRP proteins were first discovered in moths, as blood proteins that specifically bind to bacterial peptidoglycans and that mediate the activation of phenoloxidase in response to bacteria. In collaboration with Istvan Ando's lab in Szeged we are now studying other surface markers on hemocytes such as the Nimrod proteins. They are potential receptors for the phagocytosis of bacteria.
A novel persistent virus: the Nora virus. We have discovered a virus, the Nora virus, which is produced in large quantities by some Drosophila strains, apparently without causing any obvious pathology. The Nora virus is the first member of a novel family of picorna-like viruses. We are now interested in the mechanisms that regulate the persistence of this virus.
Evolution of immunity. The selection pressures on the immune system by parasites and pathogenic or harmless microorganisms have lead to a very dynamic evolution of different families of immune-related genes. The traces of this evolution can now be studied in detail thanks to recent or on-going genome projects.
Selected references
- Kylsten, P., Samakovlis, C. & Hultmark, D. The cecropin locus in Drosophila; a compact gene cluster involved in the response to infection. EMBO J. 9, 217-224 (1990).
- Engström, Y., Kadalayil, L., Sun, S.-C., Samakovlis, C., Hultmark, D. & Faye, I. κB-like motifs regulate the induction of immune genes in Drosophila. J. Mol. Biol. 232, 327-333 (1993).
- Rosetto, M., Engström, Y., Baldari, C. T., Telford, J. L. & Hultmark, D. Signals from the IL-1 receptor homolog, Toll, can activate an immune response in a Drosophila hemocyte cell line. Biochem. Biophys. Res. Commun. 209, 111-116 (1995).
- Dushay, M. S., Åsling, B. & Hultmark, D. Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila. Proc. Natl. Acad. Sci. USA 93, 10343-10347 (1996).
- Hedengren, M., Åsling, B., Dushay, M. S., Ando, I., Ekengren, S., Wihlborg, M. & Hultmark, D. Relish, a central factor in the control of humoral, but not cellular immunity in Drosophila. Mol. Cell 4, 827-837 (1999).
- Stöven, S., Ando, I., Kadalayil, L., Engström, Y. & Hultmark, D. Activation of the Drosophila NF-κB factor Relish by rapid endoproteolytic cleavage. EMBO Rep. 1, 347-352 (2000).
- Silverman, N., Zhou, R., Stöven, S., Pandey, N., Hultmark, D. & Maniatis, T. A Drosophila IκB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev. 14, 2461-2471 (2000).
- Werner, T., Liu, G., Kang, D., Ekengren, S., Steiner, H. & Hultmark, D. A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 97, 13772-13777 (2000).
- Ekengren, S., Tryselius, Y., Dushay, M. S., Liu, G., Steiner, H. & Hultmark, D. A humoral stress response in Drosophila. Curr. Biol. 11, 714-718 (2001).
- Choe, K.-M., Werner, T., Stöven, S., Hultmark, D. & Anderson KV. Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 296, 359-362 (2002).
- Kurucz, E., Zettervall, C.-J., Sinka, R., Vilmos, P., Pivarcsi, A., Ekengren, S., Hegedüs, Z., Ando, I., Hultmark, D. Hemese, a hemocyte-specific transmembrane protein, affects the cellular immune response in Drosophila. Proc. Natl. Acad. Sci. USA 100, 2622-2627 (2003).
- Werner, T., Borge-Renberg, K., Mellroth, P., Steiner, H. & Hultmark, D. Functional diversity of the Drosophila PGRP-LC gene cluster in the response to lipopolysaccharide and peptidoglycan. J. Biol. Chem. 278, 26319-26322 (2003).
- Stöven, S., Silverman, N., Junell, A., Hedengren-Olcott, M., Erturk, D., Engström, Y., Maniatis, T. & Hultmark, D. Caspase-mediated processing of the Drosophila NF-κB factor Relish. Proc. Natl. Acad. Sci. USA 100, 5991-5996 (2003).
- Zettervall, C.J., Anderl, I., Williams, M.J., Palmer, R., Kurucz, E., Ando, I., and Hultmark, D., A directed screen for genes involved in Drosophila blood cell activation. Proc Natl Acad Sci U S A 101, 14192-14197 (2004).
- Little, T.J., Hultmark, D., Read, A.F., Invertebrate immunity and the limits of mechanistic immunology. Nature Immunol. 6, 651-654 (2005).
- Habayeb, M.S., Ekengren, S.K., Hultmark, D., Nora virus, a persistent virus in Drosophila, defines a new picorna-like virus family., J. Gen. Virol. 87, 3045-3051 (2006).
- Williams, M.J., Habayeb, M.S., Hultmark, D., Reciprocal regulation of Rac1 and Rho1 in Drosophila circulating immune surveillance cells. J. Cell Sci. 120, 502-511 (2007).
- Kurucz, É., Márkus, R., Zsámboki, J., Folkl-Medzihradszky, K., Darula, Z., Vilmos, P., Udvardy, A., Krausz, I., Lukacsovich, T., Gateff, E., Zettervall, C-J., Hultmark, D., Andó, I. Nimrod, a putative phagocytosis receptor with EGF repeats in Drosophila plasmatocytes. Curr. Biol. 17, 649-654 (2007).
- Zou Z, Evans JD, Lu Z,
Zhao P, Williams M, Sumathipala N, Hetru C, Hultmark D, Jiang H.
Comparative genomic analysis of the Tribolium
immune system. Genome Biol. 8, (in press).
Reviews
- Hultmark, D. Immune reactions in Drosophila and other insects, a model for innate immunity. Trends Genet. 9, 178-183 (1993).
- Hultmark, D. Insect immunology. Ancient relationships. Nature 367, 116-117 (1994).
- Hultmark, D. Drosophila immunity: paths and patterns. Curr. Opin. Immunol. 15, 12-19 (2003)..
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Date: 2007-09-13